New autism studies find new mutations, many genes behind the disorder

Researchers have now sequenced every protein coding gene in groups of autism …

Autism clearly has a genetic component, since if one half of a set of identical twins suffers from the disorder, the other generally does as well. But there are also a high number of cases where it seems to appear spontaneously, with affected children being born in families with no history of problems.

In recent years, new molecular tools like DNA chips have allowed researchers to look at these sporadic cases in more detail. The results have suggested that spontaneous mutations may play a large role in causing the disease. But these studies were limited to looking at large changes, the loss or duplication of huge regions of the genome. Technology has marched on, however, and DNA sequencing has reached the point where we're now able to look for small individual changes in the genomes of families with an autistic member. These new studies reinforce the role of spontaneous mutations, but suggest that up to a thousand genes may be behind autistic behavior.

Three studies tackling autism with a similar approach appeared in Nature this week. They all relied on what is called "exome" sequencing. Although a lot of the body's basic biochemistry is performed by proteins, the percentage of the genome that actually encodes these proteins is very small (less than two percent). There are techniques that let us make copies of only the protein-coding portions of the genome, which are termed exons; sequencing them creates what is called an "exome." It won't capture all the genetic variation present—there are still going to be mutations in that other 98 percent, many of them significant—but it's much faster and less expensive than sequencing an entire genome.

And that's a good thing in this case, because the papers collectively sequenced a lot of people. Two of them relied on the Simons Simplex Collection, a set of families that have donated DNA from unaffected parents, affected children, and, in some cases, unaffected siblings. By comparing the exomes of a family, researchers can spot any genetic changes that arose spontaneously and only appear in affected individuals. One study sequenced 238 of these families for a total of over 900 exomes; another sequenced over 700 exomes.

The challenge with sifting through all this data is that spontaneous mutations happen all the time, and you'd expect a certain number of them to occur by chance. To really be certain that one of them was a good candidate, it would have to be mutated specifically in several individuals. Combined, the three studies identified four genes that fit the bill.

That said, a lot of the genes that were mutated only once were very intriguing. Many of them are involved in the development or maintenance of the nervous system. Sets of them clustered on the same biochemical pathways, including a signaling pathway that's essential for a lot of developmental processes. Others had previously been associated with mental disorders. In short, they look a lot like what you might expect would be behind autism, and there are a lot of them.

How many? One of the groups used a statistical analysis to estimate based on the number of genes they had identified so far. The answer they came up with is 1,034 different genes. For context, that's over four percent of the total number of estimated genes. Although there are a lot of uncertainties with this number at the moment, it does look like there are a lot of genes involved. Each one may be mutated only rarely, but it's capable of having a large effect when it is.

Two of the papers use the large and diverse collection of genes to drive home the point that autism isn't a single disorder. There may be set of behaviors and tendencies that are (more or less) common to autistics, but that isn't reflected by the biology. There's a big difference between, say, a mutation that alters how the brain develops, and one that changes the behavior of the ion channels that allow it to function once it has. We may lump those two together via a diagnosis, but we shouldn't expect that there will be a single understanding or treatment for autism.

The other thing to come out in two of the studies is support for something, apparent in epidemiological studies, that hints that the rise in diagnoses of autism isn't only a product of changed diagnoses. In general, the studies found, older fathers tended to pass on more spontaneous mutations to their kids. Since non-inherited autism appears to be a product of spontaneous mutations, a trend towards older parenthood may make autism a bit more common.

Is it Aspie of me that one of the first things I noticed is the the "Reports per 1000 children" graphic had the circles with the DIAMETER proportional the the number of reports.

Since those are circles, the actual area of the circles went up by the square of the increase, which is highly visually misleading. The actual (still notable!) increase is 6.5x, but the graphic makes it look more like 42x.

Does incidence of ASD track with economic or educational background? If so, then this jibes with the age of the parents being a factor, since (anecdote alert) more affluent couples with college degrees seem to wait longer to have their first kids. I wonder what the median age for fathers of ASD kids is vs. the median for fathers of non-ASD kids (at conception, obviously). That would also jibe with the real increase in the incidence of ASD, since (anecdote alert) more people seem to be getting college degrees and waiting longer to have kids.

As this kind of genetic testing becomes a normal diagnostic procedure for any kind of abnormal behavior a very large amount of information is going to build up that connects phenotypes with genotypes. In at least some cases, there will be homologies with organisms that are more suitable for experimental analysis than human beings. Sooner or later, we will begin to understand exactly what some of the proteins do. Once we have the big pieces in the puzzle, many of the others probably will start to fall into place.

I believe it is very much environmental - something causing genetic damage. These are too many mutations and changes in genes to not have an environmental component. It would take 2-3 generations otherwise... this is happening much faster...

I believe it is very much environmental - something causing genetic damage. These are too many mutations and changes in genes to not have an environmental component. It would take 2-3 generations otherwise... this is happening much faster...

Agreed. David Suzuki (CBC — The Nature Of Things) presented a very intriguing case for «A fresh perspective on autism research with the developing "Bacterial Theory"»

Heh, reminds me that there was a rat study some years back that resulted in behavior similar to autism when they disabled the sensory "noise filter". Basically they made the rats very sensitive to sensory stimuli of any kind.

Interesting. Yes, it's true that the age of the father has an influence, but I'm curious as to why the age of the mother is not mentioned as a relevant factor, as it does take two to conceive.

I work in Special Services, and we have seen the numbers of autistic and Down's students increase year to year. My co-workers were having a discussion of what could be causing the increase, some think that better reporting and diagnosis is a factor, some think that it's a function of an increasing population and better health care, all think that it has nothing at all to do with vaccines, but one interesting tack was brought up out of the blue: one woman thought that maybe the artificial adjustment of hormone levels due to using oral contraceptives for long periods of time had something to do with changing a woman's "stored" ova.

Before we get too far into this thread, can we please not turn it into another "these numbers are skewed and your interpretation of your ASD is wrong because it wasn't officialized?"

There's a reason why these numbers are skyrocketing, and the spectrum is wide. As I've said previously, my brother was diagnosed Autistic at 2, and it wasn't until I started living on my own and started working in larger groups of people when my traits started really showing despite tics in my speech and movement that I've known about or been made fun of since I can remember. It's hard to see specialists because you first need to be authorized by a physician, and general physicians don't understand the whole "spectrum" part. It is frustrating to hear over and over again "Well you SEEM normal! I think it's all in your head! Here's some anxiety pills!" and be shuffled along.

Interesting. Yes, it's true that the age of the father has an influence, but I'm curious as to why the age of the mother is not mentioned as a relevant factor, as it does take two to conceive.

I work in Special Services, and we have seen the numbers of autistic and Down's students increase year to year. My co-workers were having a discussion of what could be causing the increase, some think that better reporting and diagnosis is a factor, some think that it's a function of an increasing population and better health care, all think that it has nothing at all to do with vaccines, but one interesting tack was brought up out of the blue: one woman thought that maybe the artificial adjustment of hormone levels due to using oral contraceptives for long periods of time had something to do with changing a woman's "stored" ova.

On the topic of vaccines, there was a post in a CNN article a while back about Autism that I believe bears repeating.

CNN Comment wrote:

If you don't vaccinate your kids and they contract any of the listed diseases, you should be held directly liable. Period.

I have seen so many unvaccinated children with easily-preventable diseases come into the peds ward. It makes my blood boil.

Try having to tell a child that he's likely not going to survive because he parents thought the Tetanus vaccine was horrible. Then his body becomes rigid, locking up as every muscle in his body tenses and refuses to relax. He lays there, like a stiff board, barely able to move his eyes. Tears running down his face as he struggles to breathe. Then his diaphragm locks and he suffocates to death.

Anti-vaccination parents, if you've seen what I've seen, you would be ashamed of yourself.

One thing seems clear to me: there is no obvious or semi-obvious smoking gun for the changing rates of autism. So many things have been looked at, with only weak correlations. So either it's something remarkably non-obvious, or it's profoundly multi-factorial.

That said, that diagonstic rates have to be at least some of the difference. Lots more doctors know to look for spectrum traits these days. And there's a lot of resources that can become available with a diagnosis, so there's an incentive to get diagnoses.

This actually happened writh one of my kids. My oldest son was diagnosed with Aspergers in a process pushed hard by my ex-wife, and she REALLY leaned heavily on the support resources from my employer and insurance.

Once I was awarded custody of the kids, I had him reassesed, and the top autism specialist in the area determined he actually didn't come close to meeting the diagnoistic criteria for anything on the spectrum. Which was a huge deal to him, because he was really sick of seeing all these specialists (at least one appointment a DAY) for something he'd concluded on his own he didn't have.

Of course the incidents of autism are increasing. The umbrella that is used to define autism has widened continuously for years now. A friend of mine has 2 autistic kids and she has tried to tell me it hasn't changed, but there are plenty of articles showing otherwise.

Then again, she's also one of those who thinks vaccinations are evil. I didn't have seizures until I had my measles vaccination. I'm one of those 1 in 10 million the side effect for the vaccine mentions. I make sure both my daughters keep up to date on their vaccinations.

wow, what a hype suddenly over this. Announcements that all kids should be checked and bla bla bla. It's an industry creating more business (money) for itself. Feed your children less crap, more exercise. If there is actually something wrong with them, of course see a doctor.Now, can we move on?

Oh, have a listen please to this podcast called 'The No Agenda Show'. Sure, some things are with a grain of salt, but these two people make sense and also deconstruct what is actually going on here.http://www.noagendashow.com/

Interesting. Yes, it's true that the age of the father has an influence, but I'm curious as to why the age of the mother is not mentioned as a relevant factor, as it does take two to conceive.

I think they are running under the same theoretical model as others linking ASD to genetic similarities expressed in Turner's Syndrome. There is a whole genetic imprinting theory based around paternal X chromosomes.

This might help:

"Neuropsychological and molecular investigations of eight females with partial deletions of the short arm of the X chromosome indicate that the putative imprinted locus escapes X-inactivation, and probably lies on Xq or close to the centromere on Xp. If expressed only from the X chromosome of paternal origin, the existence of this locus could explain why 46,XY males (whose single X chromosome is maternal) are more vulnerable to developmental disorders of language and social cognition, such as autism, than are 46,XX females."

1148% growth rate, 10-17% annual growth? If it was only from mutations there would not be such a consistent growth, there has to be an environmental factor such as a toxin causing those supposedly random mutations to be acting in the non random exponential growth that is happening.

If it was random mutation it would be sporadic, the only thing that can cause this is a constant environmental effect. Environmental causes can be around for years whereas mutations are unpredictable and should have predictable results not the predictable constant rise we have been seeing for so many years. Never before in history have us humans been so exposed to bizzare foreign chemicals which are man made and chemicals that may have been very rare in nature are now being more commonly exposed to.

Autism is now defined so broadly that it can no longer be considered a disorder, merely a difference that conveys both advantages and disadvantages. By current standards, a very high fraction of successful scientists and engineers would be placed somewhere on the autistic spectrum. A society that managed to "cure autism" would suddenly find itself very technologically backward, with a shortage of people able to concentrate and focus deeply on highly technical matters.

Interesting. Yes, it's true that the age of the father has an influence, but I'm curious as to why the age of the mother is not mentioned as a relevant factor, as it does take two to conceive.

I work in Special Services, and we have seen the numbers of autistic and Down's students increase year to year. My co-workers were having a discussion of what could be causing the increase, some think that better reporting and diagnosis is a factor, some think that it's a function of an increasing population and better health care, all think that it has nothing at all to do with vaccines, but one interesting tack was brought up out of the blue: one woman thought that maybe the artificial adjustment of hormone levels due to using oral contraceptives for long periods of time had something to do with changing a woman's "stored" ova.

Some of the differences in male vs female contributions is the difference in the way the germ cells are formed. Female germ cell are made during development in the womb and the total for her life is made then. If one looks at the more common genetic mutation in maternally inherited chromosomes are large scale chromosomal rearrangements. Something in the long term storage of the egg cells allows for more large scale chromosomal rearrangement. The eggs are stored at the last stage of Meiosis just after Meiotic division I before the Meiotic division II. The second meiotic division is done just before ovulation of the ovum. The female Meiosis is an asymmetric cell division producing one Ovum and 3 polar bodies. In the man the meiosis cycle produces 4 sperm cells. Also duplicate chromosomes such as in Downs syndrome seem to come from the female eggs. In the paternally inherited mutation show increased short stretch chromosome rearrangement and point mutations and less large scale chromosomal rearrangement. Male sperm are produced over the life span of the male. Male primary gamete cells divide more often than in the female and for a longer period of time giving them more chances to accumulate point mutations and short stretch chromosome abnormalities.

Interesting. Yes, it's true that the age of the father has an influence, but I'm curious as to why the age of the mother is not mentioned as a relevant factor, as it does take two to conceive.

The female egg cell is only created before birth (which is why women run out), while make sperm are created throughout one's life. The older you get, the more defects there will be in the newly created sperm, I guess, which does not apply to egg cells because they were created decades ago anyway.

Telekenesis wrote:

1148% growth rate, 10-17% annual growth? If it was only from mutations there would not be such a consistent growth, there has to be an environmental factor such as a toxin causing those supposedly random mutations to be acting in the non random exponential growth that is happening.

Interesting. Yes, it's true that the age of the father has an influence, but I'm curious as to why the age of the mother is not mentioned as a relevant factor, as it does take two to conceive.

I would think the issue with age of the father rather than mover being an issue has to do with the fact that men are always making more sperm and thus old age may well cause the sperm to mutate with age where as a woman has all of her eggs from the start and age at conception shouldn't mater unless an outside force (the environment) caused the eggs to mutate for some reason.

Interesting. Yes, it's true that the age of the father has an influence, but I'm curious as to why the age of the mother is not mentioned as a relevant factor, as it does take two to conceive.

The female egg cell is only created before birth (which is why women run out), while make sperm are created throughout one's life. The older you get, the more defects there will be in the newly created sperm, I guess, which does not apply to egg cells because they were created decades ago anyway.

Telekenesis wrote:

1148% growth rate, 10-17% annual growth? If it was only from mutations there would not be such a consistent growth, there has to be an environmental factor such as a toxin causing those supposedly random mutations to be acting in the non random exponential growth that is happening.

Or more people are being diagnosed than before.

So nothing has changed and all those numbers represent better/overzealous diagnosis, and this same amount of kids with this disorder have existed but no one noticed their symptoms were autism? Right so in 10 years doctors have only been diagnosing 5 1/2 times more children and there has been no increase in actual cases. It's all doctors going batshit crazy in the last 10 years with diagnosis and before 10 years ago no one knew what autism was. If this is just diagnosis, and they knew what autism was before 1997 why is it only in the past 10 years doctors seem to be wanting to diagnose 5 1/2 more patients, why were doctors before this seemingly immune to this hysteria.

Any way you look at it, no matter how generous you try and brush it aside with rampant diagnosis there still has to be a substantial increase in real world cases meaning there has to be an environmental cause.

P.S. Interestingly, buried within the CDC report, there is an implication that that in the US by 2008 we were already in the range of 3 in 4 potentially diagnosable children already being diagnosed by age 8. That’s pretty good news, as well as a decent start on trying to establish, going forward, what portion of the increase in reported incidence rates are actual incidence rate increases and what portion is just an increase in reporting.

EDIT: Relavent discussion of that is in 2nd paragraph of "Temporal Changes in ASD Prevalence”.

I think some of the increase in diagnosis with ASD's is that it is now very much a 'go to diagnosis' for parents and doctors expressing concern with their children's social habits.

As a teacher, I have noticed that Asperger (and to a lesser extent Autism) have been on the increase. Doctors here is Asia love to brand children with these syndromes, fill them with medication and return them back to the normal school system. What actually is happening is that a student who maybe had incredibly mild social problems at school (as we all have experienced at some point in our life's) gets medicated and then winds up sitting in a back corner, spaced out and unresponsive, worse than they were before 'diagnosis'. I could state at least 10 students over the past 5-6 years I have seen this happen to. Its sad and even with school intervention mostly continues to the detriment of the students. ADHD is rapidly being replaced with Asperger Syndrome as the 'go to' diagnosis.

In the mean time, student who definitely do suffer from a ASD mostly go untreated. I have had 3 different students in my classes during my time as a teacher that definitely had Autism. They were completely unsociable, never made eye contact, language skills were none existant, could not remain still at any time, demonstrated sever ticks ... the list goes on and on. Their symptoms are extremely apparent. Only 1 on those children actually had their parents take them for official testing, and that took nearly a year of convincing. Asia has weird 'saving face' arguments for not doing this. But now that child is getting the special support he requires and seems happier in himself, with teachers feeling they can have an impact in his education as they know what they can and can't achieve with him.

I guess my point is that the chart above is all good, but like the article hits at, we need specific testing. That way children who are just children, are left as children. And those with ASD's can get the proper help they require.

Interesting. Yes, it's true that the age of the father has an influence, but I'm curious as to why the age of the mother is not mentioned as a relevant factor, as it does take two to conceive.

I would think the issue with age of the father rather than mover being an issue has to do with the fact that men are always making more sperm and thus old age may well cause the sperm to mutate with age where as a woman has all of her eggs from the start and age at conception shouldn't mater unless an outside force (the environment) caused the eggs to mutate for some reason.

Women's age at conception is directly linked to a number of genetic based health concerns for children, for example the risk of Down Syndrome. For women their 20s the probability of having a child with Down Syndrome is 1 in 1562, their late 30s it's 1 in 214, after 45 it's 1 in 19.

Could also be that the low end (also known as "high functioning") have lost their out of the way jobs, meaning that they end up having to deal with more face time and that results in more people taking notice.

Before we get too far into this thread, can we please not turn it into another "these numbers are skewed and your interpretation of your ASD is wrong because it wasn't officialized?"

There's a reason why these numbers are skyrocketing, and the spectrum is wide. As I've said previously, my brother was diagnosed Autistic at 2, and it wasn't until I started living on my own and started working in larger groups of people when my traits started really showing despite tics in my speech and movement that I've known about or been made fun of since I can remember. It's hard to see specialists because you first need to be authorized by a physician, and general physicians don't understand the whole "spectrum" part. It is frustrating to hear over and over again "Well you SEEM normal! I think it's all in your head! Here's some anxiety pills!" and be shuffled along.

Hmmm... I'm just curious as to where you live. In the public schools here, any child exhibiting social deficiencies or anything like that and they get evaluated. My mother has been a speech therapist for many years and she works with kids with autism. Parents can choose to get their children tested if they inform the school. I thought this was the norm, and also I know that private practices here you can have your children evaluated if desired.

Bunkum and rubbish. As pointed out in numerous places, the world would fall over without high-functioning autistics such as (most are speculated as Aspergers, since it wasn't diagnosed in their day) Einstein, Dan Ackroyd, Abe Lincoln, Marilyn Monroe, HP Lovecraft...

That statistic may be relevant for individuals who require full-time care, but should not be extrapolated to the entire ASD populace, many of whom (such as myself, diagnosed with Aspergers) add a great deal to society and the economy.

EHM (the alleged producer of the figures in that diagram) should not just state that ASDs are expensive. There is another side.